Factor VIII (FVIII) is a protein found in blood plasma, which acts as a cofactor in the cascade of reactions leading to blood coagulation. A deficiency in the amount of FVIII activity in the blood results in the clotting disorder known as hemophilia A, an inherited condition primarily affecting males. Hemophilia A is currently treated with therapeutic preparations of FVIII derived from human plasma or manufactured using recombinant DNA technology. Such preparations are administered either in response to a bleeding episode (on-demand therapy) or at frequent, regular intervals to prevent uncontrolled bleeding (prophylaxis).
A conventional process for manufacturing and packaging parenteral biopharmaceuticals involves the formulation of a bulk solution in accordance with the measured biological activity of the intermediate material used to formulate the bulk solution. In many cases, particularly at the end of the process, the bulk solution is frozen and stored for making the assay. For this purpose the frozen solution may be stored for several days or even for several weeks. For the subsequent filling of the final packages, such as vials, for distribution to the end users, the frozen intermediate solution is typically thawed, bulked and filled into vials, and then freeze-dried within the vials.
The amount of thawed bulk solution that is filled into the final packaging vials is calculated on the basis of the assay of the intermediate solution. This calculation usually incorporates a large safety margin because of (1) large variation of biological assay and (2) loss of yield in the subsequent sterile fill and freeze-drying process. The loss of yield is due to product stress during this first freezing, storing and thawing step and the following second filling, freezing and drying process. This calculation is of course very difficult and based on product dependent empirical knowledge of the complete process.
In conventional processes the freeze-drying is usually performed in standard freeze drying chambers which do not have temperature controlled walls. These dryers, unfortunately, provide non-homogeneous heat transfer to the vials placed in the dryer chamber. Especially those vials which are positioned at the edges exchange energy more intensively than those positioned in the center of the plates, due to radiant heat exchange and natural convection in the gap between the wall of the chamber and the stack of plates/shelves. This non-uniformity of energy distribution leads to a variation of freezing and drying kinetics between the vials at the edges and those in the center, and could result in variation in the activities of the active contents of the respective vials. To ensure the uniformity of the final product, it is necessary to conduct extensive development and validation work both at laboratory and production scales.
The publication by Wang, D. Q., MacLean, D. and Ma, X. (2010) entitled Process Robustness in Freeze Drying of Biopharmaceuticals, in Formulation and Process Development Strategies for Manufacturing Biopharmaceuticals (eds F. Jameel and S. Hershenson), John Wiley & Sons, Inc., Hoboken, N.J., USA discloses specific freeze-drying cycles for recombinant FVIII but still acknowledges potency variations as a function of the vial position in the freeze-drying chamber.
WO 2010/054238 A1 reports on a stable lyophilized pharmaceutical formulation of Factor VIII (FVIII) comprising: (a) a FVIII; (b) one or more buffering agents; (c) one or more antioxidants; (d) one or more stabilizing agents; and (e) one or more surfactants; said FVIII comprising a polypeptide selected from the group consisting of: a) a recombinant FVIII polypeptide; b) a biologically active analog, fragment or variant of a); said buffer is comprising of a pH buffering agent in a range of about 0.1 mM to about 500 mM and said pH is in a range of about 2.0 to about 12.0; said antioxidant is at a concentration of about 0.005 to about 1.0 mg/ml; said stabilizing agent is at a concentration of about 0.005 to about 20%; said surfactant is at a concentration of about 0.001% to about 1.0%; and said formulation excluding sodium chloride (NaCl) or including only trace amount of NaCl.
WO 2006/008006 A1 is concerned with a process for sterile manufacturing, including freeze-drying, storing, assaying and filling of pelletized biopharmaceutical products in final containers such as vials. A process for producing containers of a freeze-dried product is disclosed, the process comprising the steps of freezing droplets of the product to form pellets, freeze-drying the pellets, assaying the freeze-dried pellets and loading the freeze-dried pellets into containers. More specifically, the process comprises the steps of: a) freezing droplets of the product to form pellets, whereby the droplets are formed by passing a solution of the product through frequency assisted nozzles and pellets are formed from said droplets by passing them through a counter-current flow of cryogenic gas; b) freeze-drying the pellets; c) storing and homogenizing the freeze-dried pellets; d) assaying the freeze dried pellets while they are being stored and homogenized; and e) loading the freeze-dried pellets into said containers.
WO 2013/050156 A1 describes a process line for the production of freeze-dried particles under closed conditions comprising at least a spray chamber for droplet generation and freeze congealing of the liquid droplets to form particles and a bulk freeze-dryer for freeze drying the particles, the freeze-dryer comprising a rotary drum for receiving the particles. Further, a transfer section is provided for a product transfer from the spray chamber to the freeze-dryer. For the production of the particles under end-to-end closed conditions each of the devices and of the transfer section is separately adapted for operation preserving sterility of the product to be freeze-dried and/or containment.
WO 2013/050161 A1 discloses a process line for the production of freeze-dried particles under closed conditions, the process line comprising a freeze-dryer for the bulk ware production of freeze-dried particles under closed conditions, the freeze-dryer comprising a rotary drum for receiving the frozen particles, and a stationary vacuum chamber housing the rotary drum, wherein for the production of the particles under closed conditions the vacuum chamber is adapted for closed operation during processing of the particles. The drum is in open communication with the vacuum chamber and at least one transfer section is provided for a product transfer between a separate device of the process line and the freeze-dryer, the freeze-dryer and the transfer section being separately adapted for closed operation, wherein the transfer section comprises a temperature-controllable inner wall surface.